Lower alkyl esters of L-phenylalanine are preferred starting materials in the manufacture of certain sweetening agents, as disclosed in U.S. Pat. No. 3,492,131. However, heretofore those starting materials have been difficult and expensive to obtain. Due to the absence of suitable asymmetric syntheses, prior art efforts have been directed most often to the resolution of the DL-compounds.
A process for resolving alkyl esters of DL-phenylanine has been developed and disclosed in a copending application Ser. No. 395,940 of Paul B. Sollman, now U.S. Pat. No. 3,941,831, which utilizes, as intermediates, salts of the alkyl esters of L-phenylalanine and N-acyl-D-phenylalanines. Those salts are conveniently represented by the following formula ##STR1## wherein R.sub.1 is a lower alkyl radical having 1-4 carbon atoms inclusive and R.sub.2 is hydrogen or a lower alkyl radical having 1-7 carbon atoms inclusive. The salts are useful intermediates in the preparation of the lower alkyl esters of L-phenylalanine. Illustrative of these alkyl radicals intended are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl.
Other art equivalent acyl blocking groups, both aliphatic and aryl, may be utilized for r.sub.2, but the lower alkyl radicals described above are preferred.
The process is practiced preferably by contacting an alkyl ester of DL-phenylalanine in a suitable solvent with an N-acyl-D-phenylalanine; isolating and purifying the salt of the corresponding alkyl ester of L-phenylalanine and N-acyl-D-phenylalanine; decomposing the salt into its respective components; and isolating the desired alkyl ester of L-phenylalanine. The initial salt formation yields crude product which contains a quantity of undesired salt of the N-acyl-D-phenylalanine and D-phenylalanine alkyl ester.
The instant salt formation is most advantageous since it permits the N-acyl derivatives of D-phenylalanine to be utilized as the resolving agents, effecting substantial cost savings over the use of the L-isomer. Thus, the desired L-isomer of phenylalanine need not be tied up in the process. Furthermore, the crystallization of the D-L salts affords, upon purification decomposition and separation, pure product consisting of the appropriate alkyl ester of L-phenylalanine.
Typically, N-acetyl-D-phenylalanine is allowed to contact DL-phenylalanine methyl ester in a suitable solvent, e.g. methanol, ethylene chloride or water, to produce a crude crystalline salt of N-acetyl-D-phenylalanine and L-phenylalanine methyl ester. That salt is separated from the filtrate, purified and decomposed with aqueous hydrochloric acid to afford N-acetyl-D-phenylalanine as a precipitate and L-phenylalanine methyl ester hydrochloride in solution. After filtering, the solvent in the filtrate is removed to afford the hydrochloride salt of L-phenylalanine methyl ester. Alternatively, the salt of N-acetyl-D-phenylalanine and L-phenylalanine methyl ester is dissolved in aqueous potassium carbonate and extracted with ether. The D-amide remains in the aqueous phase and the L-ester is extracted into the organic phase. After phase separation, the ethereal solution is acidified with hydrochloric acid-isopropanol to precipitate the hydrochloride salt of L-phenylalanine methyl ester.
It is apparent that the starting materials useful in the process may be employed as their equivalent salts. For example, the hydrochloride salt of DL-phenylalanine methyl ester may be utilized along with the sodium salt of N-acyl-D-phenylalanine.